TLR3 Ligand Induces NF-κB Activation and Various Fates of Multiple Myeloma Cells Depending on IFN-α Production

Abstract

Multiple myeloma (MM) cells express TLR. It has been shown that TLR ligands induce the proliferation, survival, and immune surveillance escape of MM cells through MyD88-TLR pathways. Deciphering TLR function in MM cells will help in understanding the mechanisms of tumor cell growth. In this study, we examined the response of MM cells to the MyD88-independent/TIR-domain-containing adapter-inducing IFN-β-dependent TLR3. Deregulation of NF-κB pathway is a feature of MM cells, and we wondered whether TLR3 activation could mobilize the NF-κB pathway. We show that five of seven human myeloma cell line (HMCL) cells expressed TLR3. In the presence of the synthetic TLR3 ligand (poly(I:C)), activation of NF-κB pathway was observed in three of five selected TLR3+ HMCL, NCI-H929, RPMI 8226, and KMM1. In agreement with NF-κB activation, only these three HMCL responded to poly(I:C), although by either an increase (KMM1) or a decrease (NCI-H929, RPMI 8226) of proliferation. We show that KMM1 increase of proliferation was prevented by NF-κB inhibitor. In contrast, inhibition of proliferation in both NCI-H929 and RPMI 8226 was due to IFN-α-induced apoptosis. We next demonstrated that p38 MAPK pathway controlled both IFN-α secretion and IFN-α-mediated cell death. Moreover, cell death also involved activation of ERK1/2 pathway. In conclusion, our results show that TLR3 ligand induces NF-κB pathway activation in MM and support a switching function of type I IFN in the functional outcome of TLR3 triggering in tumor cells.

Downregulation of c-Myc is involved in TLR3-mediated tumor death of neuroblastoma xenografts

“…Through triggering NF-κB activation, TLR3 signal transduction may facilitate multiple myeloma cell survival. 45 It is also reported that TLR3 can promote inflammatory via mTOR to activate NF-κB in human oral keratinocytes. 46 In innate immunity, TLR3 triggers the activation of NF-κB and IRF3, generates type I interferons (IFNs) and promotes dendritic cell maturation.…”

Triggering of toll-like receptor-4 in human multiple myeloma cells promotes proliferation and alters cell responses to immune and chemotherapy drug attack

“…Moreover, our findings demonstrated that LPS-induced cell proliferation was dependent on JNK, ERK and p38 signaling, suggesting that these pathways were involved in TLR4 ligand-induced myeloma cell proliferation. Interestingly, Chiron 9 et al reported that TLR3 ligand also induced NFκB and MAPK pathway activation in MM cells. These findings suggest that different TLR ligands may induce the same or similar signaling pathway activation in MM cells and exert their effects on myeloma cell growth, survival and development of drug resistance.…”

Phosphorothioate-Modified TLR9 Ligands Protect Cancer Cells against TRAIL-Induced Apoptosis

“…TLR signaling induces Erk1/2 MAP kinase and NF-B activation in MM and colon cells that could contribute to malignant transformation (15). NF-B activation, either through mutations or interactions with the microenvironment, has been involved in the progression of many cancers, including MM (16).…”